Regulated lysosomal trafficking as a mechanism for regulating GABA_A receptor abundance at synapses in Caenorhabditis elegans

GABA_A receptor plasticity is important for both normal brain function and disease progression. We are studying GABA_A receptor plasticity in Caenorhabditis elegans using a genetic approach. Acute exposure of worms to the GABA_A agonist muscimol hyperpolarizes postsynaptic cells, causing paralysis. Worms adapt after several hours, but show uncoordinated locomotion consistent with decreased GABA signaling. Using patch-clamp and immunofluorescence approaches, we show that GABA_A receptors are selectively removed from synapses during adaptation. Subunit mRNA levels were unchanged, suggesting a post-transcriptional mechanism. Mutants with defective lysosome function (cup-5) show elevated GABA_A receptor levels at synapses prior to muscimol exposure. During adaptation, these receptors are removed more slowly, and accumulate in intracellular organelles positive for the late endosome marker GFP-RAB-7. These findings suggest that chronic agonist exposure increases endocytosis and lysosomal trafficking of GABA_A receptors, leading to reduced levels of synaptic GABA_A receptors and reduced postsynaptic GABA sensitivity.